Improving the prospects for ATMPs in Europe

With large pharma companies still reluctant to develop cell, gene and tissue-based therapies, it is critical that regulators provide proactive support to sponsors

In March 2012, the largest-ever trial of a gene therapy for cystic fibrosis (CF) was announced in the UK, with around 130 patients set to receive an inhaled therapy that will try to deliver working copies of the CF gene to the cells lining the lungs.

The medical significance of the development cannot be overstated, but what is perhaps more remarkable is that the news generated relatively little media attention and the fact that the trial was almost dropped due to lack of funding. The project was saved after the UK's Medical Research Council and National Institute for Health Research provided £3.1m in public money.

The CF gene therapy case provides a snapshot of the obstacles holding back the development of what are known in Europe as advanced therapy medicinal products (ATMPs), which is a catch-all term encompassing gene therapies, cell-based treatments and tissue-engineered products.

In fact, despite decades of research and the existence of a defined regulatory route to market in Europe for five years, the number of ATMPs on the market and in late-stage development remains vanishingly small.

A recent paper, 'Clinical development of advanced therapy medicinal products in Europe: evidence that regulators must be proactive' (Molecular Therapy 20, 479-482) authored by members of the European Medicines Agency's (EMA) Committee for Advanced Therapies (CAT), which oversees the regulation of this type of product in the EU, found that despite a constant increase in clinical trial activity in recent years 'few have reached more advanced regulatory milestones in Europe'.

CAT chair Dr Christian Schneider told PME that “despite the fact that science has progressed tremendously in these fields there is still a lot to discover and understand.”To date, only a handful of ATMPs have reached the stage of either a Marketing Authorisation Application (MAA), certification by the CAT as an ATMP or the receipt of regulatory scientific advice from the EMA, and only one has reached the market in Europe.

To understand the sector more fully, the Committee analysed clinical trial data from the EudraCT database set up in 2004 and identified 318 trials of 250 individual ATMPs, sponsored by more than 170 commercial and non-commercial organisations.

One of the main issues identified by the researchers was that most sponsors of ATMPs are academic institutions, medical charities and small companies, with very little involvement by larger pharmaceutical companies in the sector.

'This is an important finding, for these stakeholders tend to have limited resources with regard to both financing and the capacity to navigate the required regulatory procedures,' noted the paper.

It went on to argue that this caused a translational gap between development of these medicines and reaching later regulatory milestones and that regulators needed to continue working to close this gap in a proactive manner.

The paper emphasised several ways in which organisations developing ATMPs could engage in dialogue with the EMA and receive guidance on regulatory procedures. These included scientific advice, meetings with the Innovation Task Force and classification or certification of medicines as ATMPs by the CAT.

The CAT has also run focus groups to discuss aspects of the development of ATMPs with its stakeholders and organised a scientific workshop with learned societies.

This is starting to have some effect, according to Schneider: “We are starting to see a number of big pharma interested in the field, but they are perhaps engaging at a later stage during product development,” he stated.

The reasons for that reticence almost certainly relate to the numerous technical challenges facing ATMP development, including the difficulties in defining criteria for 'product identity, quality, potency or mechanism of action', as well as the need to overcome potential variability arising from manufacturing processes, according to the paper.

Among the trends identified by the CAT in its analysis were that cell-based therapies, including treatments based on both autologous or allogeneic cells, are much more commonly developed than gene therapies. This is probably because they are relatively simple to manufacture and develop and are less prone to issues plaguing gene delivery, such as a lack of efficiency and specificity for gene transfer systems and associated concerns about safety.

Schneider highlighted cell-based product, TiGenix' ChondroCelect for cartilage repair in the knee, which is a major success story for the ATMP sector as it remains the only cell-based product approved in Europe: “This chondrocyte-containing product was the first to be authorised with a European marketing authorisation and is now available to all patients in Europe,” he went on, noting that it was developed by an academic spin-off and made use of the regulatory incentives available to small and medium-sized enterprises (SMEs) in the EU.

The picture is somewhat different elsewhere in the world, for example in the US there are a number of cell-based ATMPs on the market, despite what is arguably a less-defined regulatory route to approval than in Europe.

Established products include Shire subsidiary Advanced Biohealing's Dermagraft, which is already generating sales of around $200m a year, and Novartis/Organogenesis' Apligraf, both of which are based on allogeneic cells and are used in wound healing applications such as diabetic foot ulcers.

Also recently reaching the market in the US are Fibrocell Sciences' LaViv, a fibroblast-based therapy for improving the appearance of moderate-to-severe wrinkles, Hemacord, a product based on cord blood-derived haematopoietic progenitor cells used to treat blood disorders, and Dendreon's Provenge, a therapeutic vaccine for prostate cancer.

Gene therapies account for around 22 per cent of all ATMP projects and are being developed for rare diseases typically … by small organisations

Despite some commercial progress, however, not all is rosy across the Atlantic either. In 2011, Geron called a halt to a trial of its human embryonic cell-based therapy for spinal cord injury and announced it was exiting the stem cell field entirely because of 'clinical, manufacturing and regulatory complexities'.

Meanwhile, the CAT's analysis of European clinical trials suggests that gene therapies account for around 22 per cent of all ATMP projects and are being developed for rare diseases typically, with significant unmet medical need, by small organisations. Given that the recent study 'Factors associated with success of market authorisation applications for pharmaceutical drugs submitted to the European Medicines Agency' (Eur J Clin Pharmacol 66: 39–48) found that company size is a key predictor of the likelihood of a successful regulatory outcome, it suggests these therapies 'face a high probability of failure', according to the CAT.

At the moment there is only one approved gene therapy on the market, Shenzhen SiBiono Gene Technologies' Gendicine for head and neck cancer, which is available only in China to date. Meanwhile, five others have reached the marketing submission stage, including a plasmid DNA-based therapy for peripheral vascular disease developed by Sosei and Daiichi Sankyo which has been stalled at the Japanese regulator since 2008.

On April 23, however, the gene therapy sector was dealt another blow when the EMA's Committee for Medicinal Products for Human Use (CHMP) maintained its earlier opinion that Amsterdam Molecular Therapeutics' Glybera (alipogene tiparvovec) was not approvable as a treatment for lipoprotein-lipase-deficiency, contrary to the earlier positive advice of the CAT.

It is not surprising, then, that most pharma companies are steering clear of gene therapy, with its high levels of uncertainty from a technical, clinical and regulatory perspective, according to the 2012 'Gene Therapy: A Global Strategic Business Report' from Global Industry Analysts, which calls for regulation to be harmonised on a global scale.

'With failures of gene therapies continuing worldwide and regulatory authorities being stringent and watchful, and no drug approved until now in major markets like US and Europe, the global gene therapy market has significant ground to cover,' it states, while predicting that the global market will be worth around $800m by 2017 nevertheless.

Despite the obstacles that have held back the development of the sector, Schneider remains positive about its prospects, particularly for sponsors who are concentrating on ATMPs for rare, orphan diseases.

“The development of orphan ATMPs offers many incentives and advantages because it combines the incentives offered by the Orphan Drug Regulation with the specific expertise foreseen by the ATMP regulations,” Schneider explained. Orphan drugs benefit from 10-year market exclusivity, protocol assistance and access to the centralised procedure for marketing authorisations in the EU.

He also emphasised that developers of ATMPs, and particularly academic and small commercial sponsors, should try to interact with regulators as early as possible in the development process in order to become more familiar with the “language and approach to regulation”.

“Typically the most successful products are those for which an early dialogue with regulators is initiated,” he said, noting that there are great benefits to be had by fostering increased cooperation between academic sponsors and knowledge sharing, which is already starting to happen through the creation of consortia and involvement of learned societies.

Regulators must continue to work to increase predictability of regulatory outcome, he said, noting that in the last three years the CAT had established a network of stakeholders and a platform for continuous dialogue and training.

“It is from these constructive dialogues that now we understand better the areas for improvement,” he continued, noting that the Committee was looking into specific issues including improving existing procedures such as ATMP certification and reflecting on alternative procedures.“It seems that the ATMP field is still seen as a high-risk sector [in which] to invest, but we are confident that this will change in the future,” he concluded.

The AuthorPhil Taylor is a freelance journalist specialising in the pharmaceutical industry